Targeting bromodomain-containing protein 4 (BRD4) benefits rheumatoid arthritis

Zhang, Qinggang; Qian, Jing; Zhu, Yuchang

doi:10.1016/j.imlet.2015.05.016

Cited by 48 publications

(50 citation statements)

References 32 publications

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“…1A). Consistent with our result, the pan-BETi JQ1 and BRD4 small interfering RNAs have both been reported to suppress IL-6 protein secretion from TNFa-stimulated human synovial fibroblasts (Zhang et al, 2015). Similarly, the expression of another inflammatory marker, vascular cell adhesion protein 1 (VCAM-1), was also induced with TNFa treatment, which was countered by RVX-297 administration (Fig.…”

Section: Rvx-297supporting

confidence: 88%

“…This variance may be due to differences in compound affinities for BET BDs. Results from this study and from other laboratories have shown that BET BD inhibition protects mice from autoimmunity (Belkina et al, 2013;Mele et al, 2013;Zhang et al, 2015). Therefore, BETi holds promise for the treatment of autoimmunity, even after disease symptoms have been established.…”

Section: Discussionmentioning

confidence: 51%

“…In three arthritis models, disease indices were dramatically reduced in RVX-297-treated animals, resulting in the maintenance of joint structure and integrity, likely arising from decreased production of cytokines and inflammatory mediators. The pan-BETi JQ1 is also efficacious in the mCIA model, stressing a role for BET proteins in the inflammatory response, the production of autoantibodies, and joint damage arising in this model (Zhang et al, 2015). In addition, a fundamental role for IL-17 in the CAIA model disease development has been demonstrated (Plum et al, 2009).…”

Section: Discussionmentioning

confidence: 91%

“…Small-molecule pan-BETis have been useful in delineating roles for BET BDs in inflammatory processes and autoimmune disorders (Nicodeme et al, 2010;Barrett et al, 2014;Zhang et al, 2015;Chen et al, 2016). Whereas most BETis in development have similar affinity for both (i.e., pan) BET protein BDs, RVX-297 is a novel, orally bioavailable BETi with selectivity for BD2 (Kharenko et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

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RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease

Jahagirdar

Attwell²,

Marušić³

et al. 2017

Molecular Pharmacology

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Bromodomain (BD) and extra-terminal domain containing proteins (BET) are chromatin adapters that bind acetylated histone marks via two tandem BDs, BD1 and BD2, to regulate gene transcription. BET proteins are involved in transcriptional reprogramming in response to inflammatory stimuli. BET BD inhibitors (BETis) that are nonselective for BD1 or BD2 have recognized anti-inflammatory properties in vitro and counter pathology in models of inflammation or autoimmune disease. Although both BD1 and BD2 bind acetylated histone residues, they may independently regulate the expression of BET-sensitive genes. Here we characterized the ability of RVX-297, a novel orally active BETi with selectivity for BD2, to modulate inflammatory processes in vitro, in vivo, and ex vivo. RVX-297 suppressed inflammatory gene expression in multiple immune cell types in culture. Mechanistically, RVX-297 displaced BET proteins from the promoters of sensitive genes and disrupted recruitment of active RNA polymerase II, a property shared with pan-BETis that nonselectively bind BET BDs. In the lipopolysaccharide model of inflammation, RVX-297 reduced proinflammatory mediators assessed in splenic gene expression and serum proteins. RVX-297 also countered pathology in three rodent models of polyarthritis: rat and mouse collagen-induced arthritis, and mouse collagen antibody-induced arthritis. Further, RVX-297 prevented murine experimental autoimmune encephalomyelitis (a model of human multiple sclerosis) disease development when administered prophylactically and reduced hallmarks of pathology when administered therapeutically. We show for the first time that a BD2-selective BETi maintains anti-inflammatory properties and is effective in preclinical models of acute inflammation and autoimmunity.

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Section: Rvx-297supporting

confidence: 88%

Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease

Jahagirdar

Attwell²,

Marušić³

et al. 2017

Molecular Pharmacology

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“…Many hematological cancers and solid tumors are sensitive to BET protein inhibition (45, 53). BETi also exhibit potent anti-inflammatory effects in several inflammatory disease models, including sepsis, atherosclerosis, rheumatoid arthritis, and some autoimmune diseases (28, 33, 34, 54, 55). Clinical trails with different BETi, including JQ1, against tumors and inflammation have been initiated (56).…”

Section: Discussionmentioning

confidence: 99%

BET Inhibition AttenuatesHelicobacter pylori–Induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation

Chen

Wang

et al. 2016

The Journal of Immunology

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H. pylori infection causes chronic gastritis and peptic ulceration. H. pylori-initiated chronic gastritis is characterized by enhanced expression of many NF-κB-regulated inflammatory cytokines. Brd4 has emerged as an important NF-κB regulator and regulates the expression of many NF-κB-dependent inflammatory genes. In this study, we demonstrated that Brd4 was not only actively involved in H. pylori-induced inflammatory gene mRNA transcription but also H. pylori-induced inflammatory gene eRNA synthesis. Suppression of H. pylori-induced eRNA synthesis impaired H. pylori-induced mRNA synthesis. Furthermore, H. pylori stimulated NF-κB-dependent recruitment of Brd4 to the promoters and enhancers of inflammatory genes to facilitate the RNAPII-mediated eRNA and mRNA synthesis. Inhibition of Brd4 by JQ1 attenuated H. pylori-induced eRNA and mRNA synthesis for a subset of NF-κB-dependent inflammatory genes. JQ1 also inhibited H. pylori-induced interaction between Brd4 and RelA and the recruitment of Brd4 and RNAPII to the promoters and enhancers of inflammatory genes. Finally, we demonstrated that JQ1 suppressed inflammatory gene expression, inflammation, and cell proliferation in H. pylori-infected mice. These studies highlight the importance of Brd4 in H. pylori-induced inflammatory gene expression and suggest that Brd4 could be a potential therapeutic target for the treatment of H. pylori-triggered inflammatory diseases and cancer.

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Review: Enhancers in Autoimmune Arthritis: Implications and Therapeutic Potential

Peeters

Vastert

Wijk

et al. 2017

Arthritis & Rheumatology

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Targeting bromodomain-containing protein 4 (BRD4) benefits rheumatoid arthritis

Cited by 48 publications

References 32 publications

RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease

RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease

BET Inhibition AttenuatesHelicobacter pylori–Induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation

Review: Enhancers in Autoimmune Arthritis: Implications and Therapeutic Potential

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